REVIEW EDITORIAL For reprint orders, please contact: [email protected]
Head and neck squamous cell carcinoma and human papillomavirus: epidemiology, treatment and future trends “Basic research is fundamental for translational medicine, and we must be able to give to the patients the best possible treatment option, with a precise and tailored treatment to be provided with, of note, the perfect timing and with the less adverse effects and the lowest toxicity profile possible.” Alberto Mangano*,‡,2, Alessandro Mangano‡,1, Georgios D Lianos3, Dimitrios H Roukos3, Luigi Boni2 & Gianlorenzo Dionigi2 HPV has been established as an etiological factor for head and neck squamous cell carcinoma (HNSCC); its role in the development of this condition is widely recognized [1] . This cancer has different etiological factors: in particular in the developed world this condition is associated with tobacco use and alcohol consumption [2] . In the last decades, preventive strategies have caused a significant decrease of this tumor due to alcohol and smoke use. In stark contrast, an increase in HPV-related cancers has been observed, in particular in oropharyngeal squamous cell carcinoma [3] . HNSCC represents the sixth more frequent cancer worldwide with an incidence of more than 600,000 new cases each year [4] . The burden of this condition is frequently increased by coinfection with other viruses such as HIV, HSV-1 and EBV [5] . The literature reports that individuals with HPV and concomitant coinfections with HIV and/or HSV-1 have significantly higher risk of developing HNSCC [6] .
HPV-related HNSCC: frequency, distribution & genotypes Recent papers showed that the proportion of HPV-related cancers significantly increased over the last decades; in particular a sharp increase was reported both in USA and Europe [7,8] . HPV-tonsillar cancer increased from 20% in the 1970s to more than 90% in the 2000s, what is more a similar trend was also reported for base of tongue cancer (its correlation nowadays is almost 90%) [7,8] . Moreover, HPV is detected also in nonoropharyngeal head and neck cancer, thus suggesting a role in the onset and development of cancers located in the nasopharynx [1] . A recent study conducted by Hernandez et al. [9] stated that HPV may be related to the development of a subset of laryngeal cancers. Notably, the incidence is higher among women. Furthermore, a different genotype prevalence in men and women was observed. HPV 16 and HPV 18
KEYWORDS
• head and neck squamous cell carcinoma • human papillomavirus
“...it is fundamental to continue the basic biological investigation of this cancer in order to elucidate all the aspects starting from the characterization of the tumor.”
Department of Surgical & Morphological Sciences, Insubria University, Varese, Como, Italy 1st Department of General Surgery Ospedale di Circolo e Fondazione Macchi Varese, Department of Surgical & Morphological Sciences, Insubria University, Varese, Como, Italy 3 Department of General Surgery, Ioannina University Hospital, Centre for Biosystems & Genomic Network Medicine, Ioannina University, Ioannina, Greece *Author for correspondence: [email protected] ‡ Authors contributed equally 1 2
10.2217/FON.15.17 © 2015 Future Medicine Ltd
Future Oncol. (2015) 11(6), 889–891
part of
ISSN 1479-6694
889
Editorial Mangano, Mangano, Lianos, Roukos, Boni & Dionigi
“...a better understanding of the HNSCC is a mandatory target to be reached ... to find the solutions to the currently open and unsolved problems.”
genotypes were found in men, on the contrary in women only HPV 16 genotype was detected [9] . A meta-analysis conducted analyzing the scientific papers that studied the European population from the 2002 to 2012 reported that the prevalence of HPV-related cancers in the head and neck anatomical region was globally 40% [10] . The highest association was observed in the tonsillar cancer 66.4% and, of note, lowest in pharyng (15.3%) and tongue (25.7%). Additionally, no relationship was found between HPV types and geographical setting [10] . Currently, head and neck squamous cell carcinoma is classified according to anatomic site and stage [4] resulting sometimes inefficient in detecting the biological heterogeneity of this cancer. Recently, Keck et al. published an article identifying various subtypes of HPV-related HNSSC [11] . In particular, the authors identified five subtypes of HNSCC including two biologically distinct HPV subtypes. One HPV(+) and one HPV(-) subtypes show a prominent immune and mesenchymal phenotype: a tumor infiltration with CD8 + lymphocytes is a specific feature of these inflamed/mesenchymal subtypes independent of HPV status. Those two HPV subtypes showed low expression and no copy number events for EGFR/HER-ligands and absence of EGFR/HER-ligand expression. On the contrary, the basal subtype is uniquely characterized by a prominent EGFR/HER signaling phenotype driven by multiple HER ligands, as well as strong hypoxic differentiation not seen in other subtypes [11] . This study has been able to highlight new subtypes and to better characterize and clarify HPV-related HNSCC as well as to open new ways in the treatment of this condition. In our view, it is fundamental to continue the basic biological investigation of this cancer in order to elucidate all the aspects starting from the characterization of the tumor. It is known that tumor heterogeneity is one of the main factors in treatment outcome [12] , thus a specific description of the HNSCC types plays a pivotal role in giving the possibility to develop new molecular compounds targeted to address specific cancer subtypes. Treatment options & future perspectives The infection with HPV is an important prognostic factor in HNSCC. In particular, it is a strong prognostic survival factor in patients with oropharyngeal squamous cell carcinoma [13] .
890
Future Oncol. (2015) 11(6)
Currently, treatment strategy is stage-dependent and it is mainly characterized by the following options: chemoradiotherapy, radiotherapy and surgical treatment [14] . Notably, the overall survival in patients with high-risk locoregionally advanced oropharyngeal squamous cell carcinoma is low: in particular a 3-year overall survival rate of approximatly 45% following concurrent chemoradiotherapy, compared with 93% in a low-risk group and 70.8% in an intermediate-risk group is reported [15] . These data suggest that it is important, crucial and vital to develop new customized therapies in order to increase the survival also in patients with high-risk cancers. To date, the only targeted treatment approved in Europe, USA and Japan is the cetuximab. This compound is a monoclonal antibody able to target the EGFR [4] . In fact, EGFR; ErbB1 is expressed in more than 90% of HNSCCs with high levels of EGFR protein expression being associated with a decreased survival, resistance to radiotherapy, locoregional treatment failure and higher rates of distant metastases [16] . A high expression of EGFR protein is associated with an inferior 5-year survival rate when compared with patients with HNSCC with low EGFR expression [16] . De facto, many trials investigate new therapeutic compounds in the final stages of the disease. What is more, the US FDA promotes the investigation of new molecular compounds in the preoperative window when the tumor has not developed resistance mechanisms [17] . It has been shown that, many, multiple, heterogenous and often coexisting and synergistic mechanisms are responsible for chemoresistance: among those aformentioned phenomena there are, of note, genetic and epigenetic alterations in cancer cells that may be acquired during the therapeutic treatment. Additionally, another point to ponder and a relevant element is represented by the activation of mitogenic signaling pathways, such as nuclear factor kappa-lightchain-enhancer of activated B cell [18] resulting in a reduced apoptotic rate. Moreover, the recurrence of cancers depend on a subpopulation of cancer stem cells that possess the unique and exclusive ability to self-renew and then differentiate into nontumorigenic heterogenous cell types that are able to sustain the cancer [19,20] . In the future, a better understanding of the HNSCC is mandatory target to be reached, because if we get a better understanding of those
future science group
Head & neck squamous cell carcinoma & human papillomavirus problems, a precise scientifically oriented view will be obtained and we will be able to find the solutions to the currently open and unsolved problems. In particular, we should remember Galileo Galilei’s words: “measure what is measurable, and make measurable what is not so.” De facto, it is fundamental to scientifically describe and deeply understand a phenomenon or a pathological entity (i.e., ‘measure’ it) in order to be able to develop a better, wider and targeted therapeutic strategy. In this way, our aim should be to focus and step up our efforts in the scientific investigation in order to shed light on the heterogeneity and the biological features of the HNSCC. In other words, if a deeper understanding of this topic will be reached, there will be the possibility to develop new targeted drugs capable to specifically address the cancer cells. Basic research is fundamental for translational References 1
2
Deng Z, Uehara T, Maeda H et al. Epstein– Barr virus and human papillomavirus infections and genotype distribution in head and neck cancers. PLoS ONE 9(11), e113702 (2014). Mashberg A, Boffetta P, Winkelman R, Garfinkel L. Tobacco smoking, alcohol drinking, and cancer of the oral cavity and oropharynx among U.S. veterans. Cancer 72, 1369–1375 (1993).
medicine, and we must be able to give to the patients the best possible treatment option, with a precise and tailored treatment to be provided with, of note, the perfect timing and with the less adverse effects and the lowest toxicity profile possible. In the same way, it is important to fulfill those goals in most cost-effective way possible. Financial & competing interests disclosure The authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties. No writing assistance was utilized in the production of this manuscript.
papillomavirus-related and -unrelated oral squamous cell carcinomas in the United States. J. Clin. Oncol. 26, 612–619 (2008). 8
Attner P, Du J, Nasman A, Hammarstedt L et al. The role of human papillomavirus in the increased incidence of base of tongue cancer. Int. J. Cancer 126, 2879–2884 (2010).
9
Hernandez BY, Goodman MT, Lynch CF et al. Human papillomavirus prevalence in invasive laryngeal cancer in the United States. PLoS ONE 9(12), e115931 (2014).
3
Kreimer AR, Clifford GM, Boyle P, Franceschi S. Human papillomavirus types in head and neck squamous cell carcinomas worldwide: a systematic review. Cancer Epidemiol. Biomarkers Prev. 14, 467–447 (2005).
10 Abogunrin S, Di Tanna GL, Keeping S,
4
Mangano A, Mangano A, Lianos GD, Roukos D, Caprioglio A, Dionigi G. Breakthrough targeted therapeutic approaches to squamous cell carcinoma of the head and neck. Future Oncol. 11(1), 9–12 (2015).
11 Keck MK, Zuo Z, Khattri A et al. Integrative
5
6
7
Rautava J, Kuuskoski J, Syrjanen K, Grenman R, Syrjanen S. HPV genotypes and their prognostic significance in head and neck squamous cell carcinomas. J. Clin. Virol. 53, 116–120. (2012). Smith-McCune KK, Shiboski S, Chirenje MZ et al. Type-specific cervico-vaginal human papillomavirus infection increases risk of HIV acquisition independent of other sexually transmitted infections. PLoS ONE 5, e10094 (2010). Chaturvedi AK, Engels EA, Anderson WF, Gillison ML. Incidence trends for human
future science group
Editorial
Carroll S, Iheanacho I. Prevalence of human papillomavirus in head and neck cancers in European populations: a meta-analysis. BMC Cancer. 14(1), 968 (2014). analysis of head and neck cancer identifies two biologically distinct HPV and three non-HPV subtypes. Clin. Cancer Res. doi:10.1158/1078-0432.CCR-142481 (2014) (Epub ahead of print). 12 Lianos GD, Mangano A, Rausei S, Katsios C,
Roukos DH. Tumor heterogeneity-based resistance guides personalized cancer medicine. Future Oncol. 10(12), 1889–1892 (2014). 13 Ang KK, Harris J, Wheeler R, Weber R et al.
Human papillomavirus and survival of patients with oropharyngeal cancer. N. Engl. J. Med. 363, 24–35 (2010). 14 Burtness B, Bourhis JP, Vermorken JB,
Harrington KJ, Cohen EE. Afatinib versus placebo as adjuvant therapy after
chemoradiation in a double-blind, Phase III study (LUX-Head & Neck 2) in patients with primary unresected, clinically intermediate-to-high-risk head and neck cancer: study protocol for a randomized controlled trial. Trials 15, 469 (2014). 15 Agulnik M. New approaches to EGFR
inhibition for locally advanced or metastatic squamous cell carcinoma of the head and neck (SCCHN). Med. Oncol. 29, 2481–2249 (2012). 16 Pectasides E, Rampias T, Kountourakis P
et al. Comparative prognostic value of epidermal growth factor quantitative protein expression compared with FISH for head and neck squamous cell carcinoma. Clin. Cancer Res. 17, 2947–2954 (2011). 17 Schmitz S, Ang KK, Vermorken J et al.
Targeted therapies for squamous cell carcinoma of the head and neck: current knowledge and future directions. Cancer Treat. Rev. 40, 390–404 (2014). 18 Song SH, Han SW, Bang YJ. Epigenetic-
based therapies in cancer: progress to date. Drugs 71, 2391–2403 (2011). 19 Ben-Neriah Y, Karin M. Inflammation meets
cancer, with NF-κB as the matchmaker. Nat. Immunol. 12, 715–723 (2011). 20 Weinberg RA. Maintenance of genomic
integrity and the development of cancer. The Biology of Cancer. Garland Science (Eds). Taylor and Francis Group, LLC, NY, USA, 511–572 (2014).
www.futuremedicine.com
891
Head and neck squamous cell carcinoma and human papillomavirus: epidemiology, treatment and future trends “Basic research is fundamental for translational medicine, and we must be able to give to the patients the best possible treatment option, with a precise and tailored treatment to be provided with, of note, the perfect timing and with the less adverse effects and the lowest toxicity profile possible.” Alberto Mangano*,‡,2, Alessandro Mangano‡,1, Georgios D Lianos3, Dimitrios H Roukos3, Luigi Boni2 & Gianlorenzo Dionigi2 HPV has been established as an etiological factor for head and neck squamous cell carcinoma (HNSCC); its role in the development of this condition is widely recognized [1] . This cancer has different etiological factors: in particular in the developed world this condition is associated with tobacco use and alcohol consumption [2] . In the last decades, preventive strategies have caused a significant decrease of this tumor due to alcohol and smoke use. In stark contrast, an increase in HPV-related cancers has been observed, in particular in oropharyngeal squamous cell carcinoma [3] . HNSCC represents the sixth more frequent cancer worldwide with an incidence of more than 600,000 new cases each year [4] . The burden of this condition is frequently increased by coinfection with other viruses such as HIV, HSV-1 and EBV [5] . The literature reports that individuals with HPV and concomitant coinfections with HIV and/or HSV-1 have significantly higher risk of developing HNSCC [6] .
HPV-related HNSCC: frequency, distribution & genotypes Recent papers showed that the proportion of HPV-related cancers significantly increased over the last decades; in particular a sharp increase was reported both in USA and Europe [7,8] . HPV-tonsillar cancer increased from 20% in the 1970s to more than 90% in the 2000s, what is more a similar trend was also reported for base of tongue cancer (its correlation nowadays is almost 90%) [7,8] . Moreover, HPV is detected also in nonoropharyngeal head and neck cancer, thus suggesting a role in the onset and development of cancers located in the nasopharynx [1] . A recent study conducted by Hernandez et al. [9] stated that HPV may be related to the development of a subset of laryngeal cancers. Notably, the incidence is higher among women. Furthermore, a different genotype prevalence in men and women was observed. HPV 16 and HPV 18
KEYWORDS
• head and neck squamous cell carcinoma • human papillomavirus
“...it is fundamental to continue the basic biological investigation of this cancer in order to elucidate all the aspects starting from the characterization of the tumor.”
Department of Surgical & Morphological Sciences, Insubria University, Varese, Como, Italy 1st Department of General Surgery Ospedale di Circolo e Fondazione Macchi Varese, Department of Surgical & Morphological Sciences, Insubria University, Varese, Como, Italy 3 Department of General Surgery, Ioannina University Hospital, Centre for Biosystems & Genomic Network Medicine, Ioannina University, Ioannina, Greece *Author for correspondence: [email protected] ‡ Authors contributed equally 1 2
10.2217/FON.15.17 © 2015 Future Medicine Ltd
Future Oncol. (2015) 11(6), 889–891
part of
ISSN 1479-6694
889
Editorial Mangano, Mangano, Lianos, Roukos, Boni & Dionigi
“...a better understanding of the HNSCC is a mandatory target to be reached ... to find the solutions to the currently open and unsolved problems.”
genotypes were found in men, on the contrary in women only HPV 16 genotype was detected [9] . A meta-analysis conducted analyzing the scientific papers that studied the European population from the 2002 to 2012 reported that the prevalence of HPV-related cancers in the head and neck anatomical region was globally 40% [10] . The highest association was observed in the tonsillar cancer 66.4% and, of note, lowest in pharyng (15.3%) and tongue (25.7%). Additionally, no relationship was found between HPV types and geographical setting [10] . Currently, head and neck squamous cell carcinoma is classified according to anatomic site and stage [4] resulting sometimes inefficient in detecting the biological heterogeneity of this cancer. Recently, Keck et al. published an article identifying various subtypes of HPV-related HNSSC [11] . In particular, the authors identified five subtypes of HNSCC including two biologically distinct HPV subtypes. One HPV(+) and one HPV(-) subtypes show a prominent immune and mesenchymal phenotype: a tumor infiltration with CD8 + lymphocytes is a specific feature of these inflamed/mesenchymal subtypes independent of HPV status. Those two HPV subtypes showed low expression and no copy number events for EGFR/HER-ligands and absence of EGFR/HER-ligand expression. On the contrary, the basal subtype is uniquely characterized by a prominent EGFR/HER signaling phenotype driven by multiple HER ligands, as well as strong hypoxic differentiation not seen in other subtypes [11] . This study has been able to highlight new subtypes and to better characterize and clarify HPV-related HNSCC as well as to open new ways in the treatment of this condition. In our view, it is fundamental to continue the basic biological investigation of this cancer in order to elucidate all the aspects starting from the characterization of the tumor. It is known that tumor heterogeneity is one of the main factors in treatment outcome [12] , thus a specific description of the HNSCC types plays a pivotal role in giving the possibility to develop new molecular compounds targeted to address specific cancer subtypes. Treatment options & future perspectives The infection with HPV is an important prognostic factor in HNSCC. In particular, it is a strong prognostic survival factor in patients with oropharyngeal squamous cell carcinoma [13] .
890
Future Oncol. (2015) 11(6)
Currently, treatment strategy is stage-dependent and it is mainly characterized by the following options: chemoradiotherapy, radiotherapy and surgical treatment [14] . Notably, the overall survival in patients with high-risk locoregionally advanced oropharyngeal squamous cell carcinoma is low: in particular a 3-year overall survival rate of approximatly 45% following concurrent chemoradiotherapy, compared with 93% in a low-risk group and 70.8% in an intermediate-risk group is reported [15] . These data suggest that it is important, crucial and vital to develop new customized therapies in order to increase the survival also in patients with high-risk cancers. To date, the only targeted treatment approved in Europe, USA and Japan is the cetuximab. This compound is a monoclonal antibody able to target the EGFR [4] . In fact, EGFR; ErbB1 is expressed in more than 90% of HNSCCs with high levels of EGFR protein expression being associated with a decreased survival, resistance to radiotherapy, locoregional treatment failure and higher rates of distant metastases [16] . A high expression of EGFR protein is associated with an inferior 5-year survival rate when compared with patients with HNSCC with low EGFR expression [16] . De facto, many trials investigate new therapeutic compounds in the final stages of the disease. What is more, the US FDA promotes the investigation of new molecular compounds in the preoperative window when the tumor has not developed resistance mechanisms [17] . It has been shown that, many, multiple, heterogenous and often coexisting and synergistic mechanisms are responsible for chemoresistance: among those aformentioned phenomena there are, of note, genetic and epigenetic alterations in cancer cells that may be acquired during the therapeutic treatment. Additionally, another point to ponder and a relevant element is represented by the activation of mitogenic signaling pathways, such as nuclear factor kappa-lightchain-enhancer of activated B cell [18] resulting in a reduced apoptotic rate. Moreover, the recurrence of cancers depend on a subpopulation of cancer stem cells that possess the unique and exclusive ability to self-renew and then differentiate into nontumorigenic heterogenous cell types that are able to sustain the cancer [19,20] . In the future, a better understanding of the HNSCC is mandatory target to be reached, because if we get a better understanding of those
future science group
Head & neck squamous cell carcinoma & human papillomavirus problems, a precise scientifically oriented view will be obtained and we will be able to find the solutions to the currently open and unsolved problems. In particular, we should remember Galileo Galilei’s words: “measure what is measurable, and make measurable what is not so.” De facto, it is fundamental to scientifically describe and deeply understand a phenomenon or a pathological entity (i.e., ‘measure’ it) in order to be able to develop a better, wider and targeted therapeutic strategy. In this way, our aim should be to focus and step up our efforts in the scientific investigation in order to shed light on the heterogeneity and the biological features of the HNSCC. In other words, if a deeper understanding of this topic will be reached, there will be the possibility to develop new targeted drugs capable to specifically address the cancer cells. Basic research is fundamental for translational References 1
2
Deng Z, Uehara T, Maeda H et al. Epstein– Barr virus and human papillomavirus infections and genotype distribution in head and neck cancers. PLoS ONE 9(11), e113702 (2014). Mashberg A, Boffetta P, Winkelman R, Garfinkel L. Tobacco smoking, alcohol drinking, and cancer of the oral cavity and oropharynx among U.S. veterans. Cancer 72, 1369–1375 (1993).
medicine, and we must be able to give to the patients the best possible treatment option, with a precise and tailored treatment to be provided with, of note, the perfect timing and with the less adverse effects and the lowest toxicity profile possible. In the same way, it is important to fulfill those goals in most cost-effective way possible. Financial & competing interests disclosure The authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties. No writing assistance was utilized in the production of this manuscript.
papillomavirus-related and -unrelated oral squamous cell carcinomas in the United States. J. Clin. Oncol. 26, 612–619 (2008). 8
Attner P, Du J, Nasman A, Hammarstedt L et al. The role of human papillomavirus in the increased incidence of base of tongue cancer. Int. J. Cancer 126, 2879–2884 (2010).
9
Hernandez BY, Goodman MT, Lynch CF et al. Human papillomavirus prevalence in invasive laryngeal cancer in the United States. PLoS ONE 9(12), e115931 (2014).
3
Kreimer AR, Clifford GM, Boyle P, Franceschi S. Human papillomavirus types in head and neck squamous cell carcinomas worldwide: a systematic review. Cancer Epidemiol. Biomarkers Prev. 14, 467–447 (2005).
10 Abogunrin S, Di Tanna GL, Keeping S,
4
Mangano A, Mangano A, Lianos GD, Roukos D, Caprioglio A, Dionigi G. Breakthrough targeted therapeutic approaches to squamous cell carcinoma of the head and neck. Future Oncol. 11(1), 9–12 (2015).
11 Keck MK, Zuo Z, Khattri A et al. Integrative
5
6
7
Rautava J, Kuuskoski J, Syrjanen K, Grenman R, Syrjanen S. HPV genotypes and their prognostic significance in head and neck squamous cell carcinomas. J. Clin. Virol. 53, 116–120. (2012). Smith-McCune KK, Shiboski S, Chirenje MZ et al. Type-specific cervico-vaginal human papillomavirus infection increases risk of HIV acquisition independent of other sexually transmitted infections. PLoS ONE 5, e10094 (2010). Chaturvedi AK, Engels EA, Anderson WF, Gillison ML. Incidence trends for human
future science group
Editorial
Carroll S, Iheanacho I. Prevalence of human papillomavirus in head and neck cancers in European populations: a meta-analysis. BMC Cancer. 14(1), 968 (2014). analysis of head and neck cancer identifies two biologically distinct HPV and three non-HPV subtypes. Clin. Cancer Res. doi:10.1158/1078-0432.CCR-142481 (2014) (Epub ahead of print). 12 Lianos GD, Mangano A, Rausei S, Katsios C,
Roukos DH. Tumor heterogeneity-based resistance guides personalized cancer medicine. Future Oncol. 10(12), 1889–1892 (2014). 13 Ang KK, Harris J, Wheeler R, Weber R et al.
Human papillomavirus and survival of patients with oropharyngeal cancer. N. Engl. J. Med. 363, 24–35 (2010). 14 Burtness B, Bourhis JP, Vermorken JB,
Harrington KJ, Cohen EE. Afatinib versus placebo as adjuvant therapy after
chemoradiation in a double-blind, Phase III study (LUX-Head & Neck 2) in patients with primary unresected, clinically intermediate-to-high-risk head and neck cancer: study protocol for a randomized controlled trial. Trials 15, 469 (2014). 15 Agulnik M. New approaches to EGFR
inhibition for locally advanced or metastatic squamous cell carcinoma of the head and neck (SCCHN). Med. Oncol. 29, 2481–2249 (2012). 16 Pectasides E, Rampias T, Kountourakis P
et al. Comparative prognostic value of epidermal growth factor quantitative protein expression compared with FISH for head and neck squamous cell carcinoma. Clin. Cancer Res. 17, 2947–2954 (2011). 17 Schmitz S, Ang KK, Vermorken J et al.
Targeted therapies for squamous cell carcinoma of the head and neck: current knowledge and future directions. Cancer Treat. Rev. 40, 390–404 (2014). 18 Song SH, Han SW, Bang YJ. Epigenetic-
based therapies in cancer: progress to date. Drugs 71, 2391–2403 (2011). 19 Ben-Neriah Y, Karin M. Inflammation meets
cancer, with NF-κB as the matchmaker. Nat. Immunol. 12, 715–723 (2011). 20 Weinberg RA. Maintenance of genomic
integrity and the development of cancer. The Biology of Cancer. Garland Science (Eds). Taylor and Francis Group, LLC, NY, USA, 511–572 (2014).
www.futuremedicine.com
891
